Bayesian Estimation of Tobramycin Exposure in Patients with Cystic Fibrosis

Abstract

cFixed tobramycin (mg/kg) dosing is often inappropriate in patients with cystic fibrosis (CF), as pharmacokinetics are highly variable. The area under the concentration-time curve (AUC) is an exposure metric suited to monitoring in this population. Bayesian strategies to estimate AUC have been available for over 20 years but are not standard practice in the clinical setting. To assess their suitability for use in clinical practice, three AUC estimation methods using limited sampling were compared to measured true exposure by using intensive sampling tobramycin data. Adults prescribed once daily intravenous tobramycin had eight concentrations taken over 24 h. An estimate of true exposure within one dosing interval was calculated using the trapezoidal method and compared to three alternate estimates determined using (i) a two-sample log-linear regression (LLR) method (local hospital practice); (ii) a Bayesian estimate using one concentration (AUC 1 ); and (iii) a Bayesian estimate using two concentrations (AUC 2 ). Each method was evaluated against the true measured exposure by a Bland-Altman analysis. Twelve patients with a median (range) age and weight of 25 (18 to 36) years and 66.5 (51 to 76) kg, respectively, were recruited. There was good agreement between the true exposure and the three alternate estimates of AUC, with a mean AUC bias of <10 mg/liter · h in each case, i.e., ؊8.2 (LLR), 3.8 (AUC 1 ), and 1.0 (AUC 2 ). Bayesian analysis-based and LLR estimation methods of tobramycin AUC are equivalent to true exposure estimation. All three methods may be suitable for use in the clinical setting; however, a one-sample Bayesian method may be most useful in ambulatory patients for which coordinating blood samples is difficult. Suitably powered, randomized clinical trials are required to assess patient outcomes.

Therapeutic drug monitoring: using Bayesian methods to evaluate hospital practice

“…Most patients treated with enoxaparin only had one anti‐Xa concentration measured and the estimation of PK parameters, such as clearance, may be less precise than in those who had multiple samples taken. However, it has been shown that the use of one sample when using Bayesian methods is superior than using a standard nomogram and that atypical sampling times can still provide accurate and usable results when using Bayesian methods . Accurate sampling is crucial in all forms of TDM and we recommend that guidelines clearly state optimal sampling times for all drugs.…”

“…However, it has been shown that the use of one sample when using Bayesian methods is superior than using a standard nomogram and that atypical sampling times can still provide accurate and usable results when using Bayesian methods. 28 Accurate sampling is crucial in all forms of TDM and we recommend that guidelines clearly state optimal sampling times for all drugs.…”

A Population Pharmacokinetic Model of Gentamicin in Pediatric Oncology Patients To Facilitate Personalized Dosing

“…While the log-linear regression method is more commonly used (13), it may be more invasive, tedious, and reactive in nature than Bayesian forecasting. The former requires at least 2 blood sample measurements for predictions (14), whereas Bayesian forecasting may require only 1 sample, and it is not able to give dosage predictions until a dose has first been administered. In adults with febrile neutropenia, a Bayesian approach has been shown to increase the number of patients achieving the desired target exposure to gentamicin compared to the number achieving the desired target obtained when the log-linear regression method is used (15).…”

Cystic fibrosis: novel therapies, remaining challenges

“…Even after some three decades of once daily intravenous dosing of tobramycin for acute pulmonary exacerbations, wide variations are still seen in the methods of therapeutic drug monitoring . Until recently, the software programs used in many hospitals to estimate dosing have not been validated . There is a need for the collation of data on the use of CFTR modulators in pregnancy and lactation not only to validate safety, but also because there may be a role for such therapy to prevent the complications of CF that develop in utero , such as meconium ileus, pancreatic insufficiency and congenital absence of the vas deferens.…”

“…36 Until recently, the software programs used in many hospitals to estimate dosing have not been validated. 37 There is a need for the collation of data on the use of CFTR modulators in pregnancy and lactation not only to validate safety, but also because there may be a role for such therapy to prevent the complications of CF that develop in utero, such as meconium ileus, pancreatic insufficiency and congenital absence of the vas deferens. Pharmacists have demonstrated that they can play important clinical, research and cost-saving roles in multidisciplinary CF clinics.…”